The vascular niche in aging

Cardiovascular disease (CVD) is the leading cause of death in the EU accounting for 37% of all deaths and furthermore, aging is a major risk factor of these diseases. Aging results in the progressive deterioration of the cardiac structures and compromises heart function. Although the phenotypes that arise from cardiac aging have been described, the molecular mechanisms that drive these pathological processes are just beginning to be explored. In the Institute of Cardiovascular Regeneration, we are interested in deciphering the molecular players controlling cellular aging in the different cell types present in the vascular niche of the heart like endothelial cells or pericytes (Wagner and Dimmeler, 2020). It has been found in the past decade, that the vasculature is not solely an inert barrier that prevents the leakage of blood, but that vascular cells (endothelial cells, pericytes, smooth muscle cells, etc.) are also crucial for maintaining tissue homeostasis and are involved in tissue repair in lungs, liver and the bone marrow. Since these functions are achieved by autocrine and paracrine mechanisms, the term “vascular niche” was defined.

To study the vascular niche, we use state-of-the-art molecular and cell biology approaches, including vascularized cardiac mimetic tissue (Wagner et al., 2020), cutting edge single-cell-sequencing (Tombor et al., 2021), experimental models and clinical samples. Recently, we have shown that endothelial cells modulate their function in an autocrine manner by changing laminin isoform expression pattern in the aging heart (Wagner et al., 2018) and we have described the transcriptional heterogeneity of fibroblasts identifying Serpins a key marker of cardiac aging (Vidal et al., 2019).

Recent studies revealed that aging leads to a sympathetic denervationof the left ventricle (Wagner et al. 2023) with altered neurovascular interactions as potential underlying mechanism (Wagner et al. 2023 and Manickam et al. 2025). Current studies will deepen the understanding of neurovascular interactions in the aging and diseased hearts. Furthermore, research from the institute has shown that pericytes regulate the vascular niche in ageing and that they are crucial maintaining cardiac homeostasis in the ageing heart (Tamiato et al. 2024). 

Ongoing studies in the institute have been focused on the mechanic properties of the ageing heart and their effect on different cardiac cells. We hope that our studies will open new avenues in cardiovascular research to study, analyse and reduce the cardiovascular burden associated to aging in our society.

References:

1. Tombor LS, John D, Glaser SF, Luxán G, Forte E, Furtado M, Rosenthal N, Baumgarten N, Schulz MH, Wittig J, Rogg E-M, Manavski Y, Fischer A, Muhly-Reinholz M, Klee K, Looso M, Selignow C, Acker T, Bibli S-I, Fleming I, Patrick R, Harvey RP, Abplanalp WT, Dimmeler S. 2021. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction. Nature Communications 12:681. doi:10.1038/s41467-021-20905-1
2. Vidal R, Wagner JUG, Braeuning C, Fischer C, Patrick R, Tombor L, Muhly-Reinholz M, John D, Kliem M, Conrad T, Guimarães-Camboa N, Harvey R, Dimmeler S, Sauer S. 2019. Transcriptional heterogeneity of fibroblasts is a hallmark of the aging heart. JCI Insight 4. doi:10.1172/jci.insight.131092
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4. Wagner JUG, Dimmeler S. 2020. Cellular cross-talks in the diseased and aging heart. Journal of Molecular and Cellular Cardiology 138:136–146. doi:10.1016/j.yjmcc.2019.11.152
5. Wagner JUG, Pham MD, Nicin L, Hammer M, Bottermann K, Yuan T, Sharma R, John D, Muhly-Reinholz M, Tombor L, Hardt M, Madl J, Dimmeler S, Krishnan J. 2020. Dissection of heterocellular cross-talk in vascularized cardiac tissue mimetics. Journal of Molecular and Cellular Cardiology 138:269–282. doi:10.1016/j.yjmcc.2019.12.005
6. Wagner JUG, Tombor L, Malacarne PF, Kettenhausen L-M, Panthel J, Kujundzic H, Man-ickam N, Schmitz K, Cipca M, Stilz KA, Fischer A, Muhly-Reinholz M, Abplanalp WT, John D, Mohanta S, Weber C, Habenicht A, Buchmann GK, Angendohr S, Amin E, Scherschel K, Klöcker N, Kelm M, Schüttler D, Clauss S, Guenther S, Boettger T, Braun T, Bär C, Pham M, Krishnan J, Hille S, Müller O, Bozoglu T, Kupatt C, Nardini E, Osmanagic-Myers S, Zeiher AM, Brandes RP, Luxán G, Dimmeler S. 2023. Ageing impairs the neurovascular interface in the heart. Science. 381, 897-906 (2023). doi:10.1126/science.ade4961
7. Tamiato A, Tombor LS, Fischer A, Muhly-Reinholz M, Vanicek LR, Togru BN, Neitz J, Glaser SF, Merten M, Rodriguez Morales D, Kwon J, Klatt S, Schumacher B, Guenther S, Abplanalp WT, John D, Fleming I, Wettschureck N, Dimmeler S, Luxán G. 2024. Age-dependent EGS5 loss in pericytes induces cardiac dysfunction and fibrosis. Circ Res. 134. doi:10.1161/CIRCRESAHA.123.324183